Polypharmacology represents a new and attractive approach to treat malignances, as lasting and robust efficacy could be obtained through the inhibition of multiple survival pathways with one therapeutic agent. In line with this method, we have designed a RET (rearranged during transfection) / VEGFR2 (vascular endothelial growth factor receptor 2) small molecule inhibitor that can shut down RET prosurvival signaling and VEGFR2 mediated angiogenesis. With this agent, the root of oncogenic signaling within RET-driven tumors can be shut down as well as the ability for a tumor to acquire nutrients through VEGFR2. The inhibitor can achieve activity on RET, VEGFR2, and all clinically relevant RET mutations at IC50s of = 1.0 nM. Through a PO 0.3 mg/kg/day dose, the inhibitor can block growth and cause RET-driven xenografts to shrink. Astonishingly, at a PO 3.0 mg/kg/day dose, all treated tumors recede to undetectable levels in 28 days. In xenograft models highly predictive of clinical activity, our agent is >100 times more active than similar agents. We determined inhibition of both RET and VEGFR2 in tumor xenografts and found at PO 1.0 mg/kg our agent completely blocks RET and VEGFR2 activity. Signaling to RET and VEGFR2 adaptor proteins and activation of the MAPK cascade is inhibited as well. Pathway inhibition of both RET and VEGFR2 has been correlated to observed efficacy. The inhibitor was found to be 97% bioavailable in rats with a T1/2 of ~4 hours. The agent was minimally active on hERG with IC50 of 10.0 M, CYP3A4 with IC50 = 4-10 M, and CYP2D6 with IC50 = 13 M. Inhibition of proliferative growth and proliferative signals was found highly selective for RET-driven tumors. GI50s for RET- driven tumors were typically <1.0 nM. No adverse effect was identified in a 7 day toxicity study at PO 100 mg/kg/day in mice indicating a large therapeutic window. The agent achieves activity on all ten clinically relevant RET mutations tested, including gatekeeper mutations, at IC50s = 1.0 nM. We believe the unique properties of our agent to simultaneously block all RET-driven tumor growth and suppress VEGFR2 mediated nutrient accumulation is responsible for the unparalleled efficacy, which could result in improved patient survival. In this proposal, we wish to further develop our RET/VEGFR2 dual inhibitor by completing pilot formulation, PK/PD, and toxicity studies. This will acquire pivotal data necessary to justify completing an investigative new drug (IND) package. Although we have established a robust 'proof of concept' data package, specific facets to preclinical development are lacking that warrant additional pre-IND development. With the completion of this proposal, we will have a data package that will merit full IND development.